Physioligical Genomics of Hypertensive Renal Disease

描述（由申请人提供）： 终末期肾病（ESRD）仍然是美国的一个主要健康问题。 美国，发病率一直在稳步上升， 十年超过67%的ESRD与高血压和/或 糖尿病这些关联的原因尚不清楚。不过有 越来越多的证据表明，易感基因可能发挥主要作用， 在确定一个病人？易患ESRD。我们已经开发出一种 包括遗传学、基因组学、大鼠转基因学在内的综合研究项目 和基于机制的生理学来研究 高血压和肾脏疾病易感基因。在此，我们建议 将这些工具集中用于以下具体目标：1.完成定位 Rf-1基因的克隆。我们确定了这个重要的QTL，并建议 联合收割机作图和比较基因组学定位特异基因。2. 使用微阵列确定肾脏疾病过程中涉及的途径 技术.通过鉴定在正常组织中差异表达的基因， 在ESRD发展的时间过程中，我们将看到基因是如何改变的。 表达在疾病过程中被改变。3.检验我们的假设， 由于缺乏肌源性张力，Rf-1导致肾自动调节受损， 导致肾小球高血压和肾损伤。我们还将寻求 QTL的机制研究？s Rf-2、-3和-5。4.研究Rf-1位点 通过构建携带YAC的转基因大鼠。这将允许直接测试 所有基因的信息转基因也将用于验证Rf-1。 5.使用比较基因组学研究Rf-1区域的人类同源物，Rf-1 基因和其他候选基因。使用受影响/未受影响的人 sibpairs，我们将使用SNP和序列分析来确定个体是否 表现出ESRD的患者与序列变异有显着相关性， 候选基因

DESCRIPTION (provided by applicant): End-stage renal disease (ESRD) remains a major health problem in the United States, with an incidence that has been increasing steadily for more than a decade. More than 67% of ESRD is associated with hypertension and/or diabetes. The causes for these associations are not known. However, there is increasing evidence that susceptibility genes are likely to play a major role in determining a patient?s predisposition to ESRD. We have developed a comprehensive research program including genetics, genomics, rat transgenics and mechanism-based physiology to study the complex interaction between hypertension and susceptibility genes for renal disease. Here we propose to focus these tools on the following specific aims: 1. Complete the positional cloning of the Rf-1 gene. We identified this important QTL and propose to combine mapping and comparative genomics to locate the specific gene. 2. Determine pathways involved in the renal disease process using microarray technology. By identifying genes differentially expressed in normal and diseased kidney over the time course of ESRD development, we will see how gene expression is modified in the disease process. 3. Test our hypothesis that Rf-1 causes impaired renal autoregulation due to a lack of myogenic tone, resulting in glomerular hypertension and renal damage. We will also pursue mechanism-based studies of the QTL?s Rf-2, -3 and -5. 4. Study the Rf-1 locus by constructing transgenic rats carrying YACs. This will allow a direct test of any genes within the YAC. Transgenics will also be used to validate Rf-1. 5. Use comparative genomics to study human homologue of the Rf-1 region, Rf-1 gene and other candidate genes in humans. Using affected/unaffected human sibpairs, we will use SNP and sequence analysis to determine if individuals exhibiting ESRD show a significant association with sequence variants in candidate genes.